Chronic myeloid leukemia (CML) is a myeloproliferative disease (MPD) associated with BCR-ABL, an activated tyrosine kinase that is the product of the Philadelphia chromosome. A mouse model of CML, where BCR-ABL is expressed by retroviral bone marrow transduction and transplantation, demonstrated that BCR-ABL is the direct cause of CML, and motivated the development of imatinib, an ABL kinase inhibitor that has revolutionized the treatment of CML patients. Polycythemia vera (PV), essential thromobocythemia (ET), and chronic idiopathic myelofibrosis (CIMF) are MPDs that are as prevalent as CML, but their pathogenesis is unclear, and their clinical course is complicated by bleeding, thrombosis, and progression to acute leukemia or bone marrow failure. Current therapy for these MPDs is also inadequate, ranging from phlebotomy and myelosuppressive therapy for PV and ET, to transfusions and supportive care for CIMF. Recently, a somatic activating mutation (V617F) in the JAK2 tyrosine kinase was discovered in most patients with PV and some patients with ET and CIMF. However, the role of JAK2 V617F in the pathogenesis and potential therapy of these diseases is not known. A mouse retroviral transduction/transplantation model of MPD induced by JAK2 V617F has recently been developed. Using the model, it has been demonstrated that JAK2 V617F recapitulates the entire spectrum of erythroid abnormalities of PV in mice, implicating it as the direct and principal cause of human PV. In this application, this model system will be used to address some fundamental questions about the molecular pathogenesis and therapy of JAK2 V617F-induced MPD that would be difficult or impossible to approach through human studies. Specifically, the application proposes to: (1) use a genetic approach to determine the pathways downstream of JAK2 V617F that are required for MPD, with the ultimate goal of validating additional therapeutic targets;and (2) test the therapeutic activity of molecularly targeted drugs in JAK2 V617F-induced MPD, including candidate JAK2 inhibitors. These experiments will yield new knowledge about the biology and treatment of this important group of MPDs, and should provide important information to guide the clinical development of JAK2 kinase inhibitors and other molecularly targeted therapies for MPD. Polycythemia vera (PV) is a human disease where too many red blood cells are produced. Current treatment for PV is inadequate due to blood clotting problems and development of leukemia. In this proposal, a mouse model of PV will be used to better understand the basic cause of PV, and to test new treatments for the disease. These experiments have potential to improve the quality of life for PV patients.